Reversing its own earlier decision, the FDA has informed an NMN manufacturer that the molecule can no longer be marketed as part of dietary supplements. Another company that is testing NMN as a drug probably contributed to the decision, which is not being enforced as of now.
NAD and NMN
NAD+ is a multi-role coenzyme central to metabolism. It facilitates energy production in cells and acts as a substrate for important enzymes, such as sirtuins and PARP. NAD+ levels decline with age, contributing to multiple age-related diseases [1]. Studies have confirmed various health benefits of NAD+ supplementation in animal models [2], although human trials are scarce.
NAD+ levels can be boosted via its precursors, which include nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). NMN-containing supplements have been gaining popularity in the longevity community, even though not everyone agrees on their effectiveness or safety. NMN naturally occurs in foods such as edamame, broccoli, cabbage, cucumber, and avocado.
Allowed, then banned?
Considering NMN’s popularity, the news that the FDA has effectively banned its use in dietary supplements came as a shock, especially since this had nothing to do with the molecule’s efficacy or safety.
To market a compound in dietary supplements, a company must file a new dietary ingredient (NDI) notification with the FDA. Explicit approval is not required, but if the FDA raises objections, this precludes the compound from being used in supplements.
While NMN has been sold in some markets (mainly Japan) since at least 2014, it is a relative newcomer to the US. In the past two years, several companies have filed NDI notifications, and FDA did object to them on various grounds, mostly claiming that there is insufficient proof that NMN supplementation is safe.
In 2021-2022, new human NMN studies have been published [3], which might have alleviated FDA concerns. In May, the FDA acknowledged an amended NDI notification from the China-based company SyncoZymes without objections.
However, recently, responding to another NDI notification from the company Inner Mongolia Kingdomway, the FDA changed course and declared that ß-NMN (essentially NMN) cannot be marketed as a supplement due to it already being investigated as a drug.
The FDA decision was based on a provision in the Dietary Supplement Health and Education Act of 1994 (DSHEA) stating that a dietary supplement cannot contain an ingredient that has been “authorized for investigation as a new drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public”, unless the investigations began after the ingredient had been approved for use in supplements.
A request from a pharma company
The reason for the reversal is unknown, but as reported by Natural Products Insider, in December 2021, Metro International Biotech, a startup pharmaceutical company, wrote to the FDA: “As a company that has instituted publicly available clinical trials on ß-NMN, we request that FDA take the preclusion provision … seriously to protect the rights of companies that have spent significant time and research to develop drug products from competition from dietary supplements”. According to Insider, the FDA confirmed that it had considered Metro’s request.
Metro International Biotech, co-founded by Rajendra Apte and David Sinclair, is targeting several diseases with NAD+ precursors. It has developed a proprietary version of ß-NMN called MIB-626 and asked the FDA to approve its investigation as an investigational new drug (IND).
The earliest information about an MIB-626 trial found on ClinicalTrials.gov is dated September 2021. Apparently, at least two of the three criteria needed to trigger the exclusion clause were satisfied: MIB-626 is a subject of “substantial clinical investigations” that “has been made public”. However, it is not clear when exactly the drug was authorized for investigation. According to the FDA, this depends on when the IND authorization goes into effect, but surprisingly, the FDA does not disclose this information, and it also does not immediately become public.
Will the FDA enforce this?
The FDA can decide whether to enforce its own rulings on supplements. In a notable example, NAC (N-acetyl-L-cysteine), was excluded from the definition of a dietary supplement on similar grounds in 2021, but several months later, in response to an outcry that included citizen petitions and litigation, the FDA decided to exercise enforcement discretion with regard to NAC, effectively leaving its manufacturers alone for now.
While the law (DSHEA) does not provide a rationale for the exclusion clause, it appears like it is there solely to protect pharma companies that pour massive resources into investigating new drugs. However, some could see this as unfair towards supplement companies and their clientele. In this particular case, the companies were engaged in months of back-and-forth with the FDA, addressing various concerns and amending their proposals only to have them dismissed on entirely different grounds.
Currently, there is no sign of any NMN-containing supplements being taken off the shelves, and it is not clear whether the FDA will ultimately choose to enforce its ruling. Manufacturers of NMN supplements will likely continue pressing the FDA to exercise enforcement discretion, with Metro Biotech pulling in the opposite direction.
Metro Biotech did not respond to a request for comment. An FDA spokesperson contacted by Lifespan.io did not explain the rationale behind the exclusion clause, adding that the FDA “does not comment on whether or not it has or will commence enforcement actions.”
Literature
[1] Imai, S. I., & Guarente, L. (2014). NAD+ and sirtuins in aging and disease. Trends in cell biology, 24(8), 464-471.
[2] Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., … & Yoshino, J. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell metabolism, 24(6), 795-806.
[3] Yoshino, M., Yoshino, J., Kayser, B. D., Patti, G. J., Franczyk, M. P., Mills, K. F., … & Klein, S. (2021). Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science, 372(6547), 1224-1229.
